The Thyroid Hormone Receptor-RUNX2 Axis: A Novel Tumor Suppressive Pathway in Breast Cancer

Abstract

Metastatic breast cancer is refractory to conventional therapies and is an end-stage disease. RUNX2 is a transcription factor that becomes oncogenic when aberrantly expressed in multiple tumor types, including breast cancer, supporting tumor progression and metastases. Our previous work demonstrated that the thyroid hormone receptor beta (TRβ) inhibits RUNX2 expression and tumorigenic characteristics in thyroid cells. As TRβ is a tumor suppressor, we investigated the compelling question whether TRβ also regulates RUNX2 in breast cancer. The Cancer Genome Atlas indicates that TRβ expression is decreased in the most aggressive basal-like subtype of breast cancer. We established that modulated levels of TRβ results in corresponding changes in the high levels of RUNX2 expression in metastatic, basal-like breast cells. The MDA-MB-231 triple-negative breast cancer cell line exhibits low expression of TRβ and high levels of RUNX2. Increased expression of TRβ decreased RUNX2 levels. The thyroid hormone-mediated suppression of RUNX2 is TRβ specific as TRα overexpression failed to alter RUNX2 expression. Consistent with these findings, knockdown of TRβ in non-tumor MCF10A mammary epithelial-like cells results in an increase in RUNX2 and RUNX2 target genes. Mechanistically, TRβ directly interacts with the proximal promoter of RUNX2 through a thyroid hormone response element to reduce promoter activity. The TRβ suppression of the oncogene RUNX2 is a signaling pathway shared by thyroid and breast cancers. Our findings provide a novel mechanism for TRβ-mediated tumor suppression in breast cancers. This pathway may be common to many solid tumors and impact treatment for metastatic cancers.

Common tumor‐suppressive signaling of thyroid hormone receptor beta in breast and thyroid cancer cells

“…8,9 Although the mechanisms by which TRβ represses tumorigenesis are not well-defined, TRβ is known to regulate several pathways that are drivers of cancer, including repression of PI3K signaling and repression of RUNX2 expression. 2,3,5,10,11 Our recent transcriptomic analysis in anaplastic thyroid cancer (ATC) cell line revealed TRβ functions to regulate the cancer stem cell population and induction of the JAK1/STAT1 pathway. 12 Prior studies have demonstrated that TRβ exerts a strong antitumor effect in breast cancer cells.…”

Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies

“…In brief, the work on the HECT E3s expands our understanding of the pathogenesis of hematological diseases, providing novel effectors, whose biological significance and therapeutic interest might be explored in the future, especially considering the development of precision oncology [100][101][102]. This field has opened several novel opportunities, thanks to new algorithms [103][104][105] and artificial intelligence [106], modernizing the field of precision oncology in general [107][108][109] as well as in specific cancers [110][111][112][113]. From this overview, it appears clear that further studies are needed to corroborate the implications of HECT-type E3s in leukemogenesis, to understand the molecular basis of their oncogenic function in hematological disorders, as well as to identify their relevant substrates and regulators.…”

Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

“…T3 reduced RUNX2 expression in normal and ATC cells, and TRβ knockdown increased RUNX2, increasing the expression of MMP2, MMP13, cyclin D1, osteopontin (OPN), and cadherin 6. Transfected TRβ also repressed RUNX2 and EMT markers in MDA-MB-231 cells; conversely, TRβ-knockdown in breast epithelial-like MCF10A cells caused an increase in RUNX2 and EMT markers [74]. López-Mateo et al confirmed a decrease in EMT genes such as vimentin and snail family transcriptional repressor 2 (SLUG) in estrogen receptor alpha positive (ER⍺ + ) breast cancer cells [18].…”